instmctions): A complete understanding of the thermosensory mechanisms that regulate nervous system function and be- havior requires their study in an animal with robust temperature-driven behaviors that is amenable to quantitative behavioral, physiological, and genetic analysis. When the Drosophila larva is placed in a temperature gradient, it immediately navigates towards higher or lower temperatures in pursuit of a preferred temperature range. Owing to the relative simplicity of larval motile behavior and the small size of its nervous system, behavioral and physiological analysis can be used to achieve a complete understanding of how thermosensory information is acquired and used by its neural circuits. By analyzing larval movements in response to defined thermosensory inputs, we can uncover the complete set of sensorimotor transformations that underiie thermotaxis, transformations that systematically convert specific patterns of thermosensory inputs into quantifiable patterns of motor output. The transparency of the larva body and its powerfiji genetic toolbox facilitates the use of optical neurophysiology to manipulate and monitor the activity of neural circuits throughout the lan/al nervous system. We propose to combine genetic analysis with new high-throughput behavioral assays to define the locus of themiosensation in the larval nervous system. Furthermore, combining genetic analysis with optical neurophysiology will allow us to understand the molecular pathways that shape the thermosensory properties of the specific neurons that drive cold avoidance and warm avoidance behavior. Given the high conservation of neuronal gene functions between Drosophila and higher vertebrates, we expect that results from this work will lead to major insights into more complex nervous sys-tems. RELEVANCE (See instmctions): This proposal investigates the molecular mechanisms of TRP channel-mediated thermal sensation. In humans, TRP-based thermosensation is critical for pain, inflammation and body temperature regulation. Thus, the mechanisms studied in thie proposal are of biomedical relevance. In addition, thermosensation is important for host-seeking by insect vectors of human diseases like malaria and West Nile. Thus the study of thermosensation is also relevant to the control of insect-borne human disease.